Endothelin (hereinafter referred to as “ET”) is an endogenous physiologically active peptide consisting of 21 amino acids, and known to exist as 3 types of iso-peptides, i.e., ET-1, ET-2 and ET-3, of which the amino acid sequences are slightly different each other. ET binds to the ET receptor on the target cellular membrane to exhibit a physiological activity. Up to now, as for the ET receptor, it is known that there are at least 2 sub-types, i.e., ETA and ETB. ETA receptor has higher affinity to ET-1 and ET-2 than to ET-3, and ETB receptor has the same degree of affinity to ET-1, ET-2 and ET-3.
It is reported that a potassium salt of Compound A has a chemical structure represented by the following formula (I), has a high affinity with ET receptors, particularly an ETA receptor, has an action to competitively inhibit binding to ET receptors, and is useful as a therapeutic drug for various diseases in which ET is involved, including cardiovascular diseases, such as essential hypertension (see WO 97/22595).

Example 15(a) of the foregoing document discloses a preparation process for a potassium salt of Compound A in a small amount at the laboratory level and describes that 320 mg of a potassium salt of Compound A is obtained by recrystallization from an ethanol-water mixed solvent and that the resulting crystal has a melting point of from 201 to 203° C.
Also, Example 2 of the foregoing document discloses Compound A and a preparation process in a small amount at the laboratory level as its preparation example and describes that 273 mg of Compound A is obtained by crystallization from diethyl ether as a solvent after column chromatography purification.
However, the foregoing document does not disclose or suggest at all that the potassium salt of Compound A exhibits crystal polymorphism and that a Compound A ethyl acetate and a Compound A ethanolate are stably present.
Also, for the purpose of mass-production of a potassium salt of Compound A, the present inventors made investigations about industrial manufacturing of a potassium salt of Compound A having the same quality. However, a potassium salt of Compound A having a melting point of from 201 to 203° C. as disclosed in the forgoing document could not be obtained.
Accordingly, it has been desired to establish a preparation process for a crystal of a potassium salt of Compound A having the same quality, which can be expected to have a constant operation/working-effect and is suitable as a pharmaceutical bulk drug, with good reproducibility and in high yield.
Also, though the foregoing document describes Compound A that is a process intermediate of the potassium salt of Compound A and a preparation process, since purification by a column chromatography is needed, such was not desirable on the industrial manufacturing. For this reason, it has been desired to establish a preparation process for obtaining Compound A, a salt thereof, a solvate thereof, or a solvate of a salt thereof without need of purification by a column chromatography which likely complicates the operation on the industrial manufacturing.
Disclosure of Invention
Under such technical levels, the present inventors made extensive and intensive investigations on how to provide crystals of a potassium salt of Compound A. As a result, it has surprisingly been found that a formed crystal changes depending upon the detailed preparation condition, that is, crystal polymorphism is present in the potassium salt of Compound A.
Usually, since in a compound in which crystal polymorphism is present, various properties differ depending on the crystal form, even the same compound may possibly exhibit a quite different operation/working-efficacy. In particular, in drugs, in the case where it is assumed that compounds having a different operation/working-effect have the same effect, it may be considered that an operation/working-effect that is different from one as assumed occurs, leading to an unforeseen situation. Therefore, it is demanded to provide a compound having the same quality, which can be always expected to have a constant operation/working-effect. Accordingly, in the case where a compound in which crystal polymorphism is present is used as a drug, for the sake of ensuring a uniform quality and a constant operation/working-effect required as a drug, it is necessary to provide a certain single crystal of that compound always fixedly.
In addition, as a result of further investigations on the crystal polymorphism of Compound A, novel three kinds of crystals each having a melting point different from that of the crystal of the potassium salt of Compound A disclosed in the foregoing document have been found. As a result of analysis of crystallographic data and physicochemical properties of these crystals, it has been found that any of these novel crystals have excellent properties as a pharmaceutical bulk drug, such as heat stability, solubility in aqueous solvents, biological utilization capability, and low electrification. That is, it has been found that an α-type crystal of the potassium salt of Compound A has high water solubility as compared with other two kinds of crystals and hence, is advantageous from the viewpoint of formulation, and can be expected to have an operation/working-effect such as enhancement of absorption as an oral drug; a β-type crystal of the potassium salt of Compound A has a high melting point and is excellent in heat stability; and since a γ-type crystal of the potassium salt of Compound A has a higher melting point, is low in hygroscopicity and excellent in stability, and has low electrification and high fluidity, it is excellent in industrial manufacturing, especially in filtration performance.
Also, in manufacturing general compounds, when the degree of purification of a process intermediate thereof is high, it is possible to obtain a desired compound having a high purity, and hence, such is advantageous on the preparation. However, purification using a column chromatography is not desired because it complicates the operation on the industrial manufacturing.
Here, with respect to Compound A as the process intermediate of the potassium salt of Compound A, novel two kinds of solvates, i.e., a Compound A 0.4 ethyl acetate and a Compound A monoethanolate, which do not require purification by a column chromatography that is necessary for the preparation process of Compound A described in the prior art documents during the purification, have been found. As a result of measurement of the purity of these solvates, it has been found that the purification effect of the Compound A 0.4 ethyl acetate is higher than that of the Compound A monoethanolate. Accordingly, it has been found that the Compound A 0.4 ethyl acetate is the most suitable as a process intermediate in the industrial manufacturing of the potassium salt of Compound A among Compound A, salts thereof, solvates thereof and solvates of salts thereof and that in preparing the potassium salt of Compound A, it is most industrially advantageous to employ a preparation process via the Compound A 0.4 ethyl acetate.
On the other hand, in preparing the potassium salt of Compound A using the Compound A 0.4 ethyl acetate as a process intermediate, excessive consumption of potassium hydroxide by ethyl acetate, which is used in preparing the potassium salt of Compound A as a process intermediate of Compound A, a salt thereof, a solvate thereof, or a solvate of a salt thereof, and contamination of ethyl acetate into the potassium salt of Compound A as the ultimate bulk can be prevented by preparing the potassium salt of Compound A using the Compound A monoethanolate as a process intermediate.
Accordingly, the invention has been accomplished based on these findings. According to the invention, there are provided an α-type crystal of a potassium salt of Compound A; an α-type crystal of a potassium salt of Compound A, characterized by having main peaks in the vicinity of lattice spacings of 12.00, 9.52, 4.77, 4.23 and 4.08 angstroms in the powder X-ray diffraction spectrum obtained using a Cu—Kα line; preferably, an α-type crystal of a potassium salt of Compound A, characterized having the lattice spacings and relative intensities shown in Table 1 in the powder X-ray diffraction spectrum obtained using a Cu—Kα line; and an α-type crystal of a potassium salt of Compound A having a melting point of 196 to 198° C.
TABLE 1relativelattice spacing/Åintensitylattice spacing/Årelative intensity13.42slightly strong4.23strong12.00strong4.08strong9.52strong3.87slightly strong7.46medium3.65slightly strong6.72medium3.46slightly strong5.43medium3.31medium4.77strong3.03medium
Also, according to the invention, there are provided a β-type crystal of a potassium salt of Compound A; a β-type crystal of a potassium salt of Compound A, characterized by having main peaks in the vicinity of lattice spacings of 11.65 and 4.66 angstroms in the powder X-ray diffraction spectrum obtained using a Cu—Kα line; preferably, a β-type crystal of a potassium salt of Compound A, characterized having the lattice spacings and relative intensities shown in Table 2 in the powder X-ray diffraction spectrum obtained using a Cu—Kα line; and a β-type crystal of a potassium salt of Compound A having a melting point of 231 to 233° C.
TABLE 2relativelattice spacing/Åintensitylattice spacing/Årelative intensity11.65strong4.09medium9.65medium3.99slightly strong8.60medium3.88slightly strong5.13slightly strong3.69slightly strong4.79medium3.41medium4.66strong3.17medium4.36medium3.08medium4.22slightly strong
Also, according to the invention, there are provided a γ-type crystal of a potassium salt of Compound A; a γ-type crystal of a potassium salt of Compound A, characterized by having main peaks in the vicinity of lattice spacings of 11.10, 4.92, 4.67, 4.23, 4.18, 4.10, 3.47 and 3.44 angstroms in the powder X-ray diffraction spectrum obtained using a Cu—Kα line; preferably, a γ-type crystal of a potassium salt of Compound A, characterized by having the lattice spacings and relative intensities shown in Table 3 in the powder X-ray diffraction spectrum obtained using a Cu—Kα line; and a γ-type crystal of a potassium salt of Compound A having a melting point of from 251 to 254° C.
TABLE 3relativelattice spacing/Åintensitylattice spacing/Årelative intensity11.10strong4.51slightly strong9.24medium4.23strong8.65slightly strong4.18strong4.92strong4.10strong4.87slightly strong3.47strong4.78slightly strong3.44strong4.67strong
Incidentally, in the powder X-ray diffraction spectrum, the crystal lattice spacings and overall pattern are important in approval of identity of the crystal from the viewpoint of properties of data, and since the relative intensity can somewhat change depending upon the direction of crystal growth, the size of particles, and the measurement condition, it should not be strictly considered. Also, while the invention relates to a pure α-type crystal of a potassium salt of Compound A; a pure β-type crystal of a potassium salt of Compound A; and a pure γ-type crystal of a potassium salt of Compound A, the invention also includes mixtures that can be substantially regarded in the same light as these pure α-type, β-type and γ-type crystals.
In addition, according to the invention, there are provided a Compound A ethyl acetate and a Compound A ethanolate, and preferably a Compound A 0.4 ethyl acetate and a Compound A monoethanolate, each of which is useful as a process intermediate of an α-type crystal of a potassium salt of Compound A.
Also, according to the invention, there is provided a preparation process of an α-type crystal of a potassium salt of Compound A, characterized by exerting potassium hydroxide or potassium carbonate, and preferably potassium hydroxide, to Compound A, a salt thereof, a solvate thereof or a solvate of a salt thereof, and preferably a Compound A 0.4 ethyl acetate or a Compound A monoethanolate, in an ethanol-water mixed solvent, dissolving therein, and then crystallizing out of the solution in a water-ethanol mixed solvent having a ratio of water to ethanol of 1:12.5 or more.
[Preparation Process]
The invention will be hereunder described in detail.
The α-type crystal of the potassium salt of Compound A of the invention can be prepared by adding and dissolving Compound A, a salt thereof, a solvate thereof or a solvate of a salt thereof in a solution of a reaction-corresponding amount or an excessive amount of potassium hydroxide or potassium carbonate in an ethanol-water based mixed solvent (with stirring upon heating, if desired) and after filtering insoluble materials, allowing the residue to stand for cooling and crystallization at room temperature.
At this time, since the potassium salt of Compound A has properties such that it is sparingly soluble in ethanol, in dissolving the potassium salt of Compound A in the ethanol-water based mixed solvent, it is preferable to dissolve it in a mixed solvent having a volume ratio of water to ethanol of about 1:10.
Also, during the crystallization, it is possible to obtain the α-type crystal by using a mixed solvent having a high ethanol content, to which ethanol is further added such that the volume ratio of water to ethanol is 1:12.5 or more. During this, when the dissolution, filtration and crystallization are carried out in a mixed solvent having a ratio of water to ethanol of about 1:10, the β-type crystal and γ-type crystal may possibly be formed.
Table 4 shows the melting point and solubility in water at room temperature of the three kinds of novel crystals of the potassium salt of Compound A according to the invention.
TABLE 4solubility in waterat room temperature/type of crystalmelting point/° C.mg/mLα-type crystal196–19819.3β-type crystal231–2339.0γ-type crystal251–2546.9
As a result, it was revealed that the α-type crystal of the potassium salt of Compound A is the most excellent in water solubility and that the β-type crystal and γ-type crystal have a high melting point and are excellent in heat stability.
Also, FIGS. 10 to 12 show the hygroscopicity of the three kinds of novel crystals of the potassium salt of Compound A of the invention. As a result, it was revealed that the γ-type crystal of the potassium salt of Compound A gradually absorbs moisture with an increase of the humidity but absorbs moisture only to an extent of about 1% (corresponding to 0.3 moles of water) and hence, is excellent in stability caused by the hygroscopicity. On the other hand, the α-type crystal of the potassium salt of Compound A abruptly absorbed moisture when the humidity exceeded 65%, and absorbed moisture to an extent of about 6% (corresponding to 1.8 moles of water). The β-type crystal of the potassium salt of Compound A gradually absorbed moisture when the humidity exceeded 45%, and absorbed moisture to an extent of about 4% (corresponding to 1.2 moles of water).
As to Compound A, a salt thereof, a solvate thereof or a solvate of a salt thereof, each of which is used during preparing the α-type crystal of the potassium salt of Compound A in the foregoing preparation process, it is industrially advantageous to use a Compound A 0.4 ethyl acetate or a Compound A monoethanolate, each of which does not require the purification operation by a column chromatography, as described previously.
The Compound A 0.4 ethyl acetate of the invention can be prepared by recrystallization from ethyl acetate or suspending in ethyl acetate upon heating during the purification of Compound A.
The Compound A monoethanolate can be prepared by recrystallization from ethanol or suspending in ethanol upon heating during the purification of Compound A, or by recrystallizing the Compound A 0.4 ethyl acetate from ethanol or suspending it in ethanol upon heating.
Table 5 shows the physicochemical properties of the two kinds of novel solvates of Compound A according to the invention.
TABLE 5purification effectby crystallizationmeltingmain impuritycompositionpoint/° C.purity/%content/%Compound A 0.4 ethyl acetate123–12599.20.3Compound A monoethanolate 99–10198.70.7
In Table 5, the term “main impurity” means an impurity that is most contained during the purification and is a compound represented by the following structure.
